Neoplasms

Urinary Tract, Sexual Organs, and Pregnancy Conditions

All Conditions

Uterine Cervical Neoplasms

Uterine Neoplasms

Genital Neoplasms, Female

Urogenital Neoplasms

Uterine Cervical Diseases

Uterine Diseases

Genital Diseases, Female

Genital Diseases

Urogenital Diseases

Female Urogenital Diseases

Pregnancy Complications

Female Urogenital Diseases and Pregnancy Complications

Supriya Sastri (nee Chopra), MD

Retrospective study utilizing patient data to develop and validate Machine Learning application. Available imaging data sets of patients who have completed treatment will be used to develop Normal tissue complication probability and Tumour control probability

Hypothesis Integrating existing radiation treatment information, quantitative imaging and patient outcome data from completed and ongoing clinical trials will allow development of knowledge based systems for efficient treatment delivery and allow selection of patients for intensified treatment approaches in cervix cancer.

For Aim 1. Automatic delineation of complex tumour targets for cervical cancer for the Gross Tumour Volume (GTV) at baseline and at brachytherapy and High Risk Clinical Target Volume(CTV) at baseline and brachytherapy will be done on MRI.

Following structures will be processed for automation on CT

1. Low Risk Clinical Target Volume (Low Risk CTV)
2. GTV: Nodal
3. Elective Nodal Pelvic Target Volume
4. Elective Nodal Pelvic and Paraaortic Volume
5. Rectum
6. Bladder
7. Sigmoid
8. Bowel
9. Bone Marrow

For Aim 2. The Investigator intend to employ machine learning for developing more robust normal tissue toxicity prediction models. Further advanced techniques like texture analysis of radiation dose maps and follow up tissue density will also be performed to develop predictive models of toxicity. By using our patient datasets, Investigator want to create a library of proton beam plans with the proton planning systems that will be available in department of radiation oncology and using the developed normal tissue complication plots available the information of achievable doses through protons can help in identifying patients who will benefit from proton therapy.

For Aim 3. Within this project Investigator intend to integrate staging, pathology and quantitative imaging texture features for response prediction and identification of "high risk cohort" in cervix cancer. Images and clinical data from patients that have MRI at baseline will be included The texture features can be used to categorise "good" and "poor responders" after chemoradiation. For the same cohort of patients the Investigator also have tissue available including results of additional biomarkers (like AKT,LICAM, PDL1,CD4 and CD8). The Investigator intend to first correlate difference in texture features and see if there is a pattern of different molecular features. In the second step imaging and molecular features could be integrated for developing" risk prediction models". GTV and HRCTV delineated on 150 data sets at baseline and brachytherapy within Aim 1 will be utilised to categorise responders and non-responders and validate another 150 patient data sets.

Development of Clinically High Efficient Platforms for Individualised Treatment of Cervix Cancer

Developing Clinical High Efficiency Platforms for Individualised Treatment Through Integration of Advanced Radiation Technology, Quantitative Imaging and Molecular Biology and Machine Learning for Treatment of Cervix Cancer.

1. To develop and validate automated platforms for target delineation and planning for cervix cancer in time efficient manner through

a. Machine learning based detection of abnormal cancerous tissues in multimodality medical diagnostic images.

b . To train machine base systems for automated planning of external radiation and brachytherapy for gynaecological cancers.

2. To use existing databases and radiation dose maps, imaging texture features and adverse events data for machine learning to develop "normal tissue complication plots "and to identify cervix cancer patient subgroups that may benefit from advanced radiation techniques (like proton treatment)

3. To use advanced image texture analysis within ongoing institutional and collaborative clinical trials to identify "high risk patient population" that may benefit from intensification of treatment in future

Bhabha Atomic Research Centre and Indian Institute of Technology, Mumbai.

Erasmus Medical Center

Tata Memorial Hospital

Professor, Radiation Oncology

Carcinoma

All patients are undergoing radiotherapy in Tata Medical Center

In this pilot project Investigators propose to create annotated image data bank of patients suffering from cancer. The system will provide India's first comprehensive platform to upload annotated images with associated medical and demographic information of a patient. It will support flexible query from the users with appropriate choice from a set of attributes and design of various query filters using a GUI. Over the proposed period of 18 months, images and records related to radiation oncology including pretreatment images of at least 500 patients would be annotated and archived in the data bank. The imaging modalities to be covered are X-RAY mammograms, SPECT, CT, CBCT, MR, PET-CT, Ultrasound, digital histopathology, etc. In this phase, this study will include data sets of five types of cancers namely, breast, head and neck, brain, cervix and lung cancer.

Investigator propose to demonstrate the application of this data set in cancer research. Investigator will work on serial PET-CT based radiomics of breast and cervix cancer patients to extract appropriate features and correlate them with clinico-pathological variants.

Comprehensive Digital Archive of Cancer Imaging-Radiation Oncology( CHAVI-RO )

Count of patients with complete radiological, pathological and demographic information in the CHAVI RO database.

Tata Medical Center

Infections

Symptoms and General Pathology

Immune System Diseases

Digestive System Diseases

Rare Diseases

Carcinoma, Squamous Cell

Communicable Diseases

Acquired Immunodeficiency Syndrome

HIV Infections

Microsatellite Instability

Papillomavirus Infections

HIV Seropositivity

Anus Neoplasms

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Genomic Instability

Anal Cancer

Bernard Hirschel

The molecular mechanisms involved in squamous cell carcinoma of the anus (SCCA) are poorly elucidated. HIV-positive and renal transplant patients are at high risk for developing SCCA, indicating that immune suppression plays a facilitating role. The investigators previously demonstrated that chromosomal instability (CIN) was more prevalent in SCCA of HIV-negative than HIV-positive patients. Hence, the investigators postulate that microsatellite instability (MSI), another molecular pathway, might be a feature of SCCA progression in the HIV-positive population.

Study Aims:

1. to determine the prevalence of MSI in paraffin-embedded tumor specimen of 15 patients from the Swiss HIV cohort who underwent surgical excision for SCCA; and
2. eventually, to test our hypothesis by assessing the MSI status of SCCA in 15 recently operated HIV-negative patients.

Study Design:

The study is designed in two steps:

1. Firstly, the investigators will retrieve tumor specimen from 15 HIV-positive patients, with a biopsy-confirmed diagnosis of SCCA, in three institutions. DNA from tumor and normal tissues will be extracted, and then amplified by PCR. Presence of MSI in tumors will be determined by assessing the microsatellite markers BAT25, BAT26, and CAT25.
2. Secondly, the results of molecular analysis will be compared with a population of HIV-negative patients, with the same tumors, using the same detection technique for MSI.

Background:

In the highly active antiretroviral therapy (HAART) era, the incidence of many cancers remains higher in the HIV-positive than in the general population. This is not only true for AIDS-defining malignancies, such as Kaposi's sarcoma or lymphoma, but also for other cancers, which comprise 58% of all neoplasms in a recently described US cohort \[1\]. This trend has generated renewed interest in understanding the molecular mechanisms of carcinogenesis in the immune suppressed patient. Potential explanations include prolonged survival of patients with HIV on HAART, high incidence of co-infection with oncogenic viruses, and exposure to risks such as smoking and alcohol \[2\].

Squamous cell carcinoma of the anus (SCCA) requires integration of human papillomavirus (HPV) DNA into anal canal cell chromosomes. HIV-positive men are at increased risk for developing anal cancer. A Swiss study linking the Swiss HIV cohort study and Swiss cantonal cancer registries has shown greatly elevated SIRs for anal cancer (SIR = 33.4, 95% CI = 10.5-78.6) \[3\]. Clearly, HPV-HIV coinfection plays a major role in SCCA development, but whether this contribution is associated with distinct molecular pathway of carcinogenesis, remains hypothetical \[4\].

Anal cancer occurs earlier in HIV-positive individuals (mean age 37 years) compared with HIV-negative men (58 years) and HIV-negative women (65 years). This difference of two decades in age of onset supports the hypothesis that the biology of SCCA differs between HIV-positive and HIV-negative patients \[5\]. The effect of HIV infection on the natural history of anal HPV infection is poorly understood, but most experts agree on two points: 1) 95% of HIV-positive homosexual men are co-infected with HPV; and 2) HIV infection favors persistence of HPV infection within the ano-genital tract (uterine cervix, vagina, and anal canal).

Two major and mutually exclusive types of genomic instability are involved in cancer progression. The first, known as chromosomal instability (CIN), results from a series of genetic changes, including activation of oncogenes and inactivation of tumor-suppressor genes such as p53 and APC. The second, known as microsatellite instability (MSI), results from somatic (acquired) inactivation of DNA mismatch repair genes (MMR), such as MLH1 (by hypermethylation of its promoter), typically leading to mutation of genes with coding microsatellites, such as BAT 25, BAT26 and CAT25, transforming growth factor receptor II (TGF-RII) and BAX \[6\].

MSI reflects genomewide instability (resulting from a deficient MMR system), and occurs at increased frequency in HIV-associated cervical intraepithelial and lung neoplasia. In both cases, the frequency of MSI was six fold greater in the HIV-associated tumors, compared with tumors of HIV-indeterminate patients \[7\]. Others authors have also reported a high rate of MSI in Kaposi's sarcomas and aggressive lymphomas obtained from HIV-infected patients, whereas there is no evidence of similar instability in lesions from HIV-negative patients \[8\]. The recent observation that the MSI phenotype is restricted to HIV-related lymphomas suggests that a cardinal feature of cancer, such as genetic instability, can be highly influenced by host immunity \[9\].

MSI status of SCCA in HIV-positive patients has never been investigated, but we have performed a CIN analysis of tumor specimens from 18 HIV- and 10 HIV+ patients diagnosed with SCCA in two US institutions \[10\]. Tumors in HIV-negative patients were more likely to present CIN than were tumors in HIV-positive patients (24.1% versus 6.6%, P\<0.001). Consistent loss of heterozygosity (LOH) on chromosomes 17p, 18q, 5q, and 11q was observed in HIV-negative patients with SCCA. By contrast, allelic loss at 17p, 5q, and 18q was virtually absent in tumors of HIV-positive individuals, indicating that immune suppression promote SCCA progression through an alternate pathway to CIN.

Own Research in the Field:

The applicant is a colorectal surgeon, directly involved in the treatment of patients with anorectal malignancies since 2001. He has collected preliminary data showing specific patterns of molecular aberrations in HIV-related SCCA. These findings have been published in peer-reviewed journals, with the consequence that the applicant is regularly solicited by Editors to write expert opinions and state of the art reviews in the field.

The Swiss cohort of HIV-positive patients will provide a unique opportunity to conduct this research, because of the large number of individuals already enrolled in the existing database, and the existing expertise in the field developed by Professor Hirschel and his team. A large population of patients is indeed a sine qua none condition to start this project due to the relative rarity of these tumors.

Last but not least, the molecular aspect of this research will be conducted in the laboratory of Dr Pierre Hutter, PhD, who is a leader in our country for the detection of hereditary non-polyposis colorectal cancer (HNPCC). Thus, Dr Hutter laboratory will provide an excellent environment to perform the molecular analyses described herein.

Study Hypotheses:

We hypothesize that, in the HIV population, microsatellite instability, rather than chromosomal instability, is the favoured pathway for rapid progression of anal intra-epithelial neoplasia towards invasive SCCA. The second hypothesis is that, by comparison, MSI is either absent or at least very rare in SCCA of HIV-negative individuals.

Study Aims and Objectives

The primary objective of this study is to assess microsatellite instability status in tumor specimens of 15 HIV-positive patients from the Swiss Cohort who were diagnosed with SCCA; an interim analysis will then be performed to determine the incidence of MSI in SCCA of HIV-positive patients. If a majority of tumours exhibit MSI in this population, we will proceed with the second part of the study, which objective is to perform the same analyses in similar tumors of 15 HIV-negative patients, and thus to compare the molecular profiles of SCCA in both populations. By doing so, the potential role of immune suppression in carcinogenesis progression might be established.

Study Design and Plan

Patients:

Patients from the Swiss HIV cohort with a biopsy-proven diagnosis of squamous cell carcinoma of the anus will be identified using the existing database. We choose to analyse at least 15 samples, depending on availability, between 3 SHCS centers. Tumors from HIV-negative patients who underwent surgery for SCCA will be retrieved from the Department of Pathology of University Hospital Geneva, pending review of the protocol by the local Ethics Committee.

Intervention:

All tumor samples will be reassessed for confirmation of diagnosis by a pathologist. For each patient, paraffin blocks with both tumor tissue and normal mucosa will be selected for DNA extraction and polymerase chain reaction at microsatellite targets. The tissues were routinely collected from the operating room, fixed in buffered formalin, embedded in paraffin, and stored for a variable number of months prior to selection for analysis. Paraffin-embedded blocks will be cut with a microtome into 20-µm thick sections. Using a sterile scalpel blade, areas of normal (non-tumor) and cancer tissue will be microdissected under a dissecting microscope utilizing a haematoxylin and eosin-stained section as a guide. The specimens will be deparaffinised in toluol, purified with absolute ethanol, and centrifuged at 14,000 rpm. Previous experience in Dr Hutter's laboratory has demonstrated that it is indeed technically possible to perform this type of molecular analysis in paraffin-embedded tumour specimen.

We will use the reference panel of microsatellite primers recommended for colorectal cancer specimens to determine the presence of microsatellite instability in SCCA. These include the microsatellite markers BAT25, BAT26, as well as CAT25.

Study Evaluations:

Initial evaluation of data will be performed after analysis of the first 15 tumours specimen. If MSI is detected in the HIV-positive population, further investigation will be conducted in tumors of HIV-negative patients. Data analysis will be subject to progress reports conducted with all investigators at regular intervals. We chose to restrict, at least initially, our analysis to 15 tumours for three reasons:

1. This is a relatively rare cancer, and it is unlikely that we will be able to retrieve more than 25 SCCA patients from the Swiss HIV cohort.
2. Our previous study was conducted with 18 tumours specimen in each group, and the differences between groups were statistically significant.
3. This is a pilot exploratory study, and the working hypothesis may prove wrong; it is therefore critical to limit the initial costs in accordance with the study budget and availability of Dr Hutter's expertise. If our hypothesis is supported by the initial results, we may proceed with additional investigations and a more elaborated research project with adequate funding resources.¨ For these reasons, we will restrict our research to three SHCS centers. Zurich, Geneva and Lausanne were chosen essentially based on existing relationship between the visceral surgery units.

Data Analysis:

MSI status of tumors will be assessed by Pierre Hutter. The results will then be correlated with the epidemiological data from the Swiss cohort, and correlated with the patients' clinical characteristics, including viral load, CD4+ count, as well as clinical outcome. The results will also be correlated with treatment outcome and cancer survival.

Time Frame:

Tumor specimen will be retrieved from the Departments of Pathology in Lausanne, Geneva and Zurich in the beginning of 2009. The MSI analysis is a straightforward procedure, which takes about 24 hours in the laboratory of Dr Hutter. Thus, the analysis of the 15 specimen in the HIV-positive population will be completed by the end of March 2009. Further decision regarding subsequent analyses in the HIV-negative population will then be subjected to decision, according to the results obtained in these initial tumors.

Status of Ethical Approval:

Patients enrolled in the Swiss HIV cohort study initially gave their consent for participating in this type of study. Almost all patients at the HIV centres consented to take part in genetic research in order to identify specific factors that might result in differences in the course of the disease. Obviously, all analyses will be performed on tumor specimen, and these will not be traceable to the patients' identities. Thus, all genetic testing will be totally anonymous. By contrast, further approval by the local Ethics Committee in Geneva will be sought, should the analysis be performed on tumor specimen from HIV-negative patients.

Study budget:

The initial analysis of 15 HIV-positive patients will be performed free of charge by Pierre Hutter. The cost for molecular study is estimated at 250.-CHF per case. Thus, in case the analysis of MSI in this group leads to promising results, it is estimated that the cost of analysis in 12-15 HIV-negative patients will cost around 3,000.-CHF. Funding for this type of research will be available through the Fonds de Service of Department of Surgery at University Hospital Geneva.

Molecular Biology of Anal Cancer in HIV-Positive Patients

Microsatellite Instability in Anal Squamous Cell Carcinomas of HIV-Positive Versus HIV-Negative Patients

University of Lausanne Hospitals

University of Zurich

University Hospital, Geneva

Pascal Gervaz

Skin and Connective Tissue Diseases

Breast Neoplasms

Breast Diseases

Skin Diseases

All Drugs and Chemicals

Fluorodeoxyglucose F18

non interventional study

Patricia de Cremoux, MD-PhD

David Groheux, MD-PhD

David Groheux, MD-PHD

matthieu resche-rigon, MD-PHD

Ingrid Veron

A correlation between early changes in the tumor maximum standardized uptake value (SUVmax) on FDG-PET after one or two cycles of neoadjuvant chemotherapy (NAC) and the pathological response after 6 to 8 cycles has been demonstrated in several independent small series of patients.

Breast tumor proliferation status has previously been demonstrated to be a good predictive factor of response to chemotherapy. The best method for assessing proliferation status is unclear. Proportion of cells staining for nuclear Ki67 antigen is the most widely used assay for comparing the proliferation status between tumors. However major variations in analytical procedure and interpretation limited its clinical value. Taking into account the prognosis and predictive value of proliferation gene as a common "signature" in breast cancer transcriptome analysis, quantitative assessment of mRNA expression of genes involved in proliferation has been developed by the investigators team and others. The evaluation of these parameters is quantitative and reliable and can be standardized for a clinical use.

The main objective of the investigators study is to early predict pathological response to anthracycline-based neoadjuvant chemotherapy (NAC) using a combination of parameters based on FDG-PET imaging performed at baseline and after 2 cycles, and molecular markers of proliferation measured on pre-treatment biopsy (Ki67 protein level by immunohistochemistry and Ki67 mRNA level and the mRNA (messenger RNA) expression of the most pertinent genes of the Genomic Grade Index (GGI) component by RT (reverse transcriptase) - qPCR).

Assessment of Breast Cancer Response to Neoadjuvant Anthracycline-based Chemotherapy by FDG-PET and Molecular Markers

Assessment of Breast Cancer Response to Neoadjuvant Anthracycline-based Chemotherapy by Fluorodeoxyglucose Positron Emission Tomography (FDG-PET) and Molecular Markers

* To analyze separately clinical, pathological and molecular biomarkers currently used to identify molecular breast cancer subgroups of the primary tumor that, coupled with the metabolic response, could improve early pathological prediction.
* To analyze separately the biological, molecular, and genetic biomarkers from the study that, coupled with the metabolic response, could improve early pathological prediction.
* To analyze separately high throughput analysis of molecular biomarkers of the primary tumor that, coupled with the metabolic response, could improve early pathological prediction.

To determine the 5 years Event free survival (EFS) rates in breast cancer patients according to PET response, biological markers and biomarkers identified with molecular high throughput analysis.

To determine the 3 years Event free survival (EFS) rates in breast cancer patients according to PET response, biological markers and biomarkers identified with molecular high throughput analysis.

To determine the 5 years Breast Cancer Specific survival rates in breast cancer patients according to PET response, biological markers and biomarkers identified with molecular high throughput analysis.

To determine the 3 years Breast Cancer Specific survival rates in breast cancer patients according to PET response, biological markers and biomarkers identified with molecular high throughput analysis.

To evaluate the correlation between baseline molecular status of proliferation and FDG uptake measured at baseline, after 2 cycles of NAC and the change (delta SUV).

Assistance Publique - Hôpitaux de Paris

Colonic Neoplasms

Adenoma

Colonic Polyps

Polyps

Colorectal Neoplasms

Intestinal Neoplasms

Gastrointestinal Neoplasms

Digestive System Neoplasms

Gastrointestinal Diseases

Colonic Diseases

Intestinal Diseases

Rectal Diseases

Pathological Conditions, Anatomical

Intestinal Polyps

Herbal and Botanical

Cola

Individuals scheduled for colonoscopy at Hospital Universitari i Politècnic La Fe, participating in the Valencian CRC screening program, will be recruited.

Polypectomy or biopsy will be performed if necessary (following current guidelines).

Specific molecular analysis of serrated lesions and CRC will be carried out.

A colonoscopy will be performed to all individuals.

Colonoscopy

All lesions will be removed or biopsied during the procedure

Polypectomy or biopsy

Molecular analysis will be performed in all colorectal cancers and in those polyps diagnosed with "serrated lesion"

Molecular analysis

Marco Bustamante, M.D.;Ph.D.

Different subtypes of serrated lesions have been recently described. Among them, both sessile serrated polyp/adenoma (SSP/A) and traditional serrated adenoma (TSA) could have malignant potential through the serrated pathway or CIMP. These lesions, as a potential source of interval cancer, should also be considered in colorectal cancer (CRC) population-based screening programs. It is believed that this new described pathway could be responsible for up to 30% of all CRC.

Unlike the traditional adenoma, serrated lesions are difficult to diagnose because of their particular endoscopic appearance and their still unclear histological criteria. Furthermore, they have specific molecular changes and, through them, they could evolve into CRC faster than the adenoma. The real prevalence of the serrated lesions and their specific risk for developing new synchronous/metachronous lesions, or even malignancy, remains unknown. For all these reasons, we don't know if these patients could constitute a different CRC-risk group and if specific recommendations are needed during their follow-up.

This is a prospective longitudinal study developed within the framework of the CRC-screening program in the Valencian Community (Spain). We expect to include a total of 700 individuals who will be followed during 10 years.

In our study, we will collect epidemiologic variables related to the patient, variables related to all the polyps, and mutational (BRAF, KRAS, MSI), and CpG-island methylation status of serrated lesions. Strict endoscopic and histological criteria will be applied for the diagnosis of serrated lesions. All lesions detected at the index colonoscopy and during follow-up will be evaluated.

The purpose of this study is to correlate epidemiologic data, histological characteristics and the molecular profile of the serrated lesions with findings during follow-up, in order to define stratified groups according to their risk of developing new lesions or CRC in the future.

BACKGROUND Colorectal cancer (CRC) is, by its frequency and consequences, a relevant public health problem that has led to the implementation of population screening programs in many countries. The purpose of these programs is to reduce the incidence and mortality of CRC by early diagnosis of the disease, in the so-called pre-symptomatic phase. That is, to identify and remove all precursor lesions, essentially colon adenomas.

However, there is increasing evidence that these programs are not fully effective in preventing CRC. Cancers that appear before the next scheduled endoscopic control, called interval cancer (IC), occur in up to 2.5 / 1000 patients / year of observation, and the cumulative probability of developing a CRC within the first 5 years after an adenoma removal could be up to 2%. Recent studies suggest that the cause of more than 50% of ICs is the failure detecting premalignant lesions in the colon, either due to a poor colon preparation, technical deficiencies in the performance of colonoscopy or the characteristics of the lesions that make them barely visible.

A possible origin of the ICs could be the serrated polyp (SP). This is actually not a single lesion, but a heterogeneous group of lesions, different from the conventional adenoma, and characterized by the serration of the crypts in the histology. Serrated lesions, especially some subgroups, have macroscopic features that make them particularly difficult to detect in conventional colonoscopy: indistinct borders, cloud-like appearance, often covered by a mucous cap and interruption of the underlying mucosal vascular pattern. But the true diagnosis of serrated lesions is made by morphological criteria with the microscopic examination of the sample obtained by biopsy. Although all lesions that showed these features were initially identified as hyperplastic polyps (HP), in the last decade three subtypes of serrated lesions with different clinical implications have been described \[HP, sessile serrated polyp/adenoma (SSA/P) and traditional serrated adenoma (TSA)\]. However, the histological criteria are not yet fully clarified, and there is confusion in the terms to be used. Therefore, the agreement among pathologists is generally poor.

As a consequence, many serrated lesions are misdiagnosed and incorrectly classified. This has clinical relevance since some of them have malignant capacity. Both SSA/P and TSA can evolve to CRC through the so-called serrated pathway or cytosine-phosphate-guanosine (CpG) island methylator phenotype (CIMP), which could be responsible for up to 30% of all CRC. In this pathway, an aberrant hypermethylation of the genome is produced, which leads to transcriptional silencing and inhibition of expression in some genes promoter regions (epigenetic modification). CRCs that arise from a SP are not homogeneous and may have different molecular and histological characteristics depending on whether the origin mutation in the precursor lesion occurs in BRAF or Kirsten rat sarcoma (KRAS) gene, which leads to the development of SSA/P or TSA. And depending on if a mutL homolog 1 (MLH1) gene methylation is produced thereafter, a unstable (MSI) or stable (MSS) CRC will develop. The presence of a high CIMP rate also depends on the initial mutation. Therefore, serrated lesions could originate MSI/CIMP-H CRC (11%), MSS/CIMP-H CCR (4%) and MSS/CIMP-L CRC (15%). It is thought that some of the ICs may be directly related to the SP because they share morphological and molecular characteristics. The evolution from SSP/SSA to invasive carcinoma has been described to occur in only eight months.

This theoretical risk of developing advanced premalignant lesions and IC and its clinical significance has not been clearly shown in clinical practice because data on the prevalence of serrated lesions are limited and there is also a lack of longitudinal follow-up studies in patients with serrated lesions. The prevalence described is very variable and ranges from 0.6% to 13%, depending on the study, and the data are even scarcer in fecal occult blood test (FOBT) -based screening population. The presence of serrated lesions (other than HP) has been associated with the development of advanced synchronous adenomas in the colon, but also with advanced metachronous lesions during follow-up. This situation could place these patients in a special risk group. Patients with large SP may have a similar risk to develop a future CRC to those patients with advanced adenomas. Most Scientific Societies recommend endoscopic follow-up of serrated lesions, but the evidence is weak and specific intervals are proposed based only on expert recommendations.

In summary, there are still many unresolved questions about serrated polyps and their importance in CRC screening programs. Their prevalence on CRC screening population is not fully clarified because of the lack of prospective trials and the difficulty in diagnosis and histological classification. Their malignant potential is not clarified either because of the uncertainty about the prevalence of dysplasia in serrated lesions, and the lack of well-designed longitudinal studies for the detection of metachronic lesions. The current criteria for classifying these lesions seem weak to define the CRC risk for a specific patient, thus the proposed follow-up intervals are not based on strong scientific evidence. A thorough study of serrated lesions relating their molecular and histological characteristics with lesions found on colonoscopic follow-up could establish a new molecular classification aimed to design a patient-oriented follow-up strategy.

HYPOTHESIS The correlation of epidemiological data of the patient, histological characteristics and molecular alterations of SP of the colon, along with findings in the endoscopic follow-up, would allow to identify stratified groups of patients according to their risk of developing advanced lesions and CRC in the future.

OBJECTIVE

* To deepen the knowledge of histology and genetic alterations of SP and thereby try to establish a molecular classification that may serve as a basis for new endoscopic follow-up guidelines. These recommendations would be more reliable and adjusted to the patient's individual risk profile.
* To establish the prevalence of serrated lesions, especially SSP/SSA and SSP with dysplasia, in the FOBT positive CRC screening population.

colonic polyp or colorectal cancer samples

Molecular and Histological Characteristics of Serrated Lesions of the Colon

Molecular and Histological Characteristics of Serrated Lesions of the Colon: Development of an Individual Risk Profile Applicable to Population-based Colorectal Cancer Screening Programs

To assess the risk of developing metachronous advanced lesions or cancers in FOBT screening population

Analysis of molecular changes in colorectal cancer and serrated lesions in FOBT screening population

To assess the prevalence of serrated lesions in FOBT screening population

Hospital Universitario La Fe

Gastrointestinal Endoscopy Consultant

Samples will be taken as part of routine care consultations. These include

* Smears taken with cytobrushes adapted to the anatomical site (cervix, vulva, vagina, penis, anus, upper aerodigestive tract...).
* Blood samples taken to isolate plasma, cells or serum.
* CSF and effusion samples taken with a suitable puncture needle (lumbar puncture, ascites puncture, pleural puncture, etc.).
* Urine samples collected in sterile ECBU jars.
* Biopsies taken according to the recommendations of good clinical practice using specific forceps adapted to the anatomical site.
* Surgical parts.
* Eyebrows.
* Saliva samples or gargle samples.

Molecular biology

Jean-Luc PRETET

In oncology, the search for genetic alterations or infectious agents in tumour tissues has become a major medical challenge for diagnosis, prognosis, prediction of response to treatment and in particular to targeted therapies, or for the biological monitoring of the disease. Over the last ten years, the development of new molecular biology tools based on high-throughput technologies has enabled us to revisit our conceptions of the development and natural history of cancers. The use of these tools has also allowed the dismemberment of numerous cancerous pathologies according to their molecular etiologies and oncogenetic histories. These new molecular biology tools have thus contributed to the emergence of so-called personalised or precision medicine.

It is in this context the prescription of targeted therapies is now conditioned by the identification of specific genetic anomalies in the tumour. As such, kinase inhibitors have been shown to be effective in patients with non-small cell lung cancer or metastatic melanoma when mutations in epidermal growth factor receptor (EGFR) or BRAF, respectively, are identified. Conversely, the identification of KRAS or NRAS mutation in metastatic colon cancers predicts resistance to anti-EGFR antibody-based therapies. Under these conditions, the prescription of these targeted therapies provides a major benefit to patients. The efficacy of these therapies is linked to the fact that the target mutations are "driver" mutations delivering a powerful oncogenic signal. These mutations are also an 'Achilles heel' for the tumour cell, which becomes hypersensitive to certain tyrosine kinase inhibitors. However, tumour escape from targeted therapies is well documented after a few months of treatment. Here again, molecular analysis of progressing tumours has revealed intratumoural heterogeneity with, in particular, the appearance of secondary mutations responsible, at least in part, for the development of resistance. This is why it is important to characterise the molecular profile of tumours both during the natural history of the disease and in treated patients in order to offer them appropriate follow-up.

Among the 170 human papillomaviruses (HPV) described in 2013, a dozen or so so-called high-risk or oncogenic HPVs are responsible for all cervical cancers, almost all anal cancers, half of vulvar and vaginal cancers and certain cancers of the upper aerodigestive tract. While HPV infection is necessary for cancer to develop, it is not sufficient and co-factors that promote persistent infection increase the risk of developing precancerous lesions and then cancers. Thus, the natural history of infection by these viruses is closely linked to that of the cancer they induce. The molecular mechanisms of HPV-related carcinogenesis/transformation are well described. It is the combined action of two viral proteins (E6 and E7) on the two tumour repressors p53 and pRb that initially lifts the intrinsic mechanisms of replicative senescence of the cell (which thus acquires the capacity to divide indefinitely), and then gradually leads to its transformation. However, the determinants that lead an infected cell to immortalise and then transform remain poorly understood and the vast majority of infections are eliminated spontaneously within 10 to 18 months following the development of effective immune responses. It is likely that host (immunosuppression, genetic factors), viral, and environmental (smoking, oral contraception) co-factors will influence the carcinogenesis process. Thus, it is recognised that HPV16 is the most carcinogenic genotype. It is the longest persisting HPV and is associated with the highest risk of developing pre-cancer or cervical cancer. Cervical cancers associated with HPV16 (or HPV18/45) have been shown to have a worse prognosis than those infected with other genotypes. Conversely, in upper aerodigestive tract cancers, those induced by an HPV (this is HPV16 in more than 95% of cases), have a better prognosis than those not induced by a virus. Thus, genotyping a tumour to identify the type of HPV involved could be of clinical interest, particularly depending on the location of the tumour.

The therapeutic management of patients with HPV-associated cancers most often consists of a combination of surgery and/or radiochemotherapy (cis-platinum, 5-fluorouracil) depending on the extent of the tumour. For anal cancers, work in Bisonne showed that the addition of a third chemotherapy molecule (taxane) was very promising as it allowed previously unobserved remissions. The reasons for such efficacy are not clear, nor is there a predictor of response to treatment.

Molecular genetic analyses are carried out using various types of samples such as cells from smears or punctures, biopsies, surgical parts and numerous fluids such as urine, cerebrospinal fluid or blood. While the standard for molecular diagnosis today is to analyse the tumour sample, the use of a "liquid biopsy" from a simple blood sample is widely considered. Indeed, it has now been shown that cancers release DNA that can be detected in the blood of patients, this is circulating tumour DNA. Thus, it is possible to diagnose or perform biological monitoring of cancers (e.g. before/after treatment) from a liquid biopsy. However, the study of circulating tumour DNA still faces some difficulties. Firstly, the concentration of circulating DNA is very low, in the order of a few tens of nanograms per mL of plasma. Furthermore, the vast majority of circulating DNA is composed of DNA released from normal cells and the proportion of circulating tumour DNA is only 1-4% of circulating DNA. Finally, circulating tumour DNA is generally fragmented (\<200 bp). In order to overcome these constraints, it is necessary to use highly sensitive techniques, both to measure the concentration of circulating DNA and to search for molecular alterations characteristic of the tumour. In this respect, circulating tumour DNA analysis brings a new dimension to the management of cancer patients. Based on circulating tumour DNA analysis, it is possible to direct treatment towards a targeted therapy in the absence of a tissue biopsy, to assess the effectiveness of a treatment, to follow the evolution of the disease, and even to identify recurrence. Circulating tumour DNA analysis also provides a snapshot of all genetic alterations in the tumour (primary and metastatic) reflecting tumour heterogeneity, whereas biopsy results are only representative of the site from which they were taken. For HPV-associated cancers, viral genome detection from liquid biopsies is also largely feasible. However, studies are still needed today to not only validate the principle of liquid biopsy in cancers, but also to clarify its clinical utility. Recent results have shown that changes in plasma HPV viral load predict response to treatment.

Since the sequencing of the human genome in 2001, DNA analysis techniques have progressed enormously and the new 'next generation sequencing' (NGS) technologies allow the simultaneous analysis of a very large number of genes (several hundred) from several dozen different samples. These sequencing capabilities make it possible to rapidly explore a large number of genetic anomalies at a lower cost. Data on genetic abnormalities in HPV-associated cancers exist and it has been very recently reported that HPVs are also subject to genetic variations during the carcinogenesis process.

Technological advances in molecular biology (high-throughput sequencing, digital PCR, circulating tumour DNA) now make it possible to describe very precisely any genetic or epigenetic modifications that could constitute potential biomarkers. A better description of these genetic modifications in sequential samples during the transition between a normal state, a precancer and a cancer as a function of time will make it possible to develop, on the one hand, models predicting the appearance of cancers and, on the other hand, innovative tools for diagnosis and risk stratification of developing a cancer. It will be possible to propose early medical interventions only for those patients who need them. The study of genetic abnormalities in patients treated for cancer will make it possible to propose innovative tools for monitoring the disease, predicting relapse or cure or identifying new therapeutic or vaccine targets.

This is why the investigators want to be able to collect biological samples of various kinds (smears, biopsies, biological fluids, etc.), whether they have been taken in the context of care or stored in declared collections (tumour libraries, for example). These samples will be collected and stored at the Besançon University Hospital in the form of a collection (MOCA collection) which will be associated with clinical data. The investigators will then be able to build up homogeneous cohorts of patients from this collection from which the investigators can study theranostic biomarkers.

Molecular Markers in Cancers and Precancers (MOCA)

Molecular Markers in Cancers and Precancers

Somatic mutations will be identified from precancer and cancer tissues from different localisations and from circulating DNA by NGS.

DNA methylation patterns will be identified from precancer and cancer tissues from different localisations and from circulating DNA by NGS or methylation specific PCR.

HPV genotypes will be identified from precancer and cancer tissues from different localisations and from circulating DNA by NGS or multiplex PCR.

HPV viral load will be assessed from precancer and cancer tissues from different localisations and from circulating DNA by real-time PCR or ddPCR.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Development of Clinically High Efficient Platforms for Individualised Treatment of Cervix Cancer	NCT05102240	Cervix Cancer		18 Years - 90 Years	Tata Memorial Hospital
Comprehensive Digital Archive of Cancer Imaging-Radiation Oncology( CHAVI-RO )	NCT04249895	All Cancer		-	Tata Medical Center
Development of Clinically High Efficient Platforms for Individualised Treatment of Cervix Cancer	NCT05102240	Cervix Cancer		18 Years - 90 Years	Tata Memorial Hospital
Comprehensive Digital Archive of Cancer Imaging-Radiation Oncology( CHAVI-RO )	NCT04249895	All Cancer		-	Tata Medical Center
Molecular Biology of Anal Cancer in HIV-Positive Patients	NCT00952874	Carcinoma HIV Infections		20 Years - 80 Years	University Hospital, Geneva
Assessment of Breast Cancer Response to Neoadjuvant Anthracycline-based Chemotherapy by FDG-PET and Molecular Markers	NCT02600442	Breast Neoplasm... Breast Cancer	non interventio...	-	Assistance Publique - Hôpitaux de Paris
Molecular and Histological Characteristics of Serrated Lesions of the Colon	NCT03089268	Colonic Neoplas... Colorectal Canc... Sessile Serrate... Polyp of Colon	Colonoscopy Polypectomy or ... Molecular analy...	50 Years - 75 Years	Hospital Universitario La Fe
Development of Clinically High Efficient Platforms for Individualised Treatment of Cervix Cancer	NCT05102240	Cervix Cancer		18 Years - 90 Years	Tata Memorial Hospital
Assessment of Breast Cancer Response to Neoadjuvant Anthracycline-based Chemotherapy by FDG-PET and Molecular Markers	NCT02600442	Breast Neoplasm... Breast Cancer	non interventio...	-	Assistance Publique - Hôpitaux de Paris
Molecular Markers in Cancers and Precancers (MOCA)	NCT05257707	Cancer Precancerous Le... Healthy	Molecular biolo...	18 Years -	Centre Hospitalier Universitaire de Besancon

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